Mutation

In biology, a mutation is any physical change in the genetic material of an organism. In most organisms, including humans, the genetic material is DNA, while some viruses use RNA. Mutations can be caused by internal or external factors. In multicellular organisms there are two primary classes of mutation, germline mutations and somatic mutations. Germline mutations are those changes that can be passed down to offspring, while somatic mutations are mutations that only alter genetic material in the mutated organism. Somatic mutations are the root cause of cancer. There is some evidence that changes outside of the cell's genetic material, such as the cytoplasm, proteins, or the cell membrane can also be inherited.

Common external factors include ultraviolet radiation, chemical mutagens, or parasitic organisms (such as viruses or bacteria). Most internal causes of mutations stem from errors in reproduction of genetic material.

Some organisms will respond to harsh environments by increasing the rate of mutations. This is known as hypermutation and is hypothesized to aid organisms by creating wider variation in the gene pool of the population, increasing the chances that at least some descendents might survive under harsh conditions. Hypermutation also occurs in the human immune system, so that our antibodies have more variation and can respond to a greater variety of invaders.

Classes of mutations

DNA is not a static entity. It is subject to a variety of different types of heritable change (mutation). Large-scale chromosome abnormalities involve loss or gain of chromosomes, or breakage and rejoining of chromatids. Smaller scale mutations can be grouped into different mutation classes according to the effect on the DNA sequence. Mutations can also be categorized on the basis of whether they involve a single DNA sequence or whether they involve exchanges between two allelic or non-allelic sequences. According to molecular pathology, there are three main classes of mutation with several subclasses: deletions, insertions and substitutions.

Deletion mutations

Deletion mutations are mutations where part of a chromosome or DNA sequence is missing.

Insertion mutations

Insertion mutations are mutations where DNA is inserted into the genetic sequence.

Substitution mutations

A point mutation or substitution is the most limited type of mutation, whereby a single base nucleotide is replaced with another nucleotide.

For example, sickle-cell anemia is caused by a single point mutation in one allele of the beta hemoglobin gene, whereby a CCT codon is converted into TCT. The TCT then mistakenly encodes the amino acid serine instead of proline.

Sometimes the expression "point mutation" can also include the addition or subtraction of a single base pair, which is also referred to as an "indel".

Deletions and insertions can also occur on a large scale. Other large-scale genetic changes include inversions, where an entire stretch of DNA is removed from the chromosome and replaced in the opposite direction; translocations, where DNA is moved from one part of the genome to another; and duplication, where a region of DNA is copied multiple times and re-inserted into the genome (for example, an entire chromosome is duplicated in Down syndrome).

Mutation subclasses

The following is a list of mutation subclasses that can fall into the three major classes of mutation.

Morphological

Morphological mutants affect the outward appearance of an individual (phenotype). Plant height mutations could changes a tall plant to a short one, or from having smooth to round seeds, due to mutations in genes relating to plant growth.

Biochemical

Biochemical mutations have a lesion in a gene necessary for one specific step of an enzymatic pathway. For bacteria, biochemical mutants need to be grown on a media supplemented with a specific nutrient. Such mutants are called auxotrophs. Often though, morphological mutants are the direct result of a mutation in a biochemical pathway. In humans, albinism is the result of a mutation in the pathway from converts the amino acid tyrosine to the skin pigment melanin. Similarly, cretinism results when the tyrosine to thyroxine pathway is mutated. Therefore, in a strict genetic sense, if appropriate experiments are performed, a morphological mutation can be explained at the biochemical level.

For some mutations to be expressed, the individual needs to be placed in a specific environment. This is called the restrictive condition. But if the individual grow in any other environment (permissive condition), the wild type phenotype is expressed. These are called conditional mutations. Mutations that only expressed at a specific temperature (temperature sensitive mutants), usually elevated, can be considered to be conditional mutations.

Lethal

Lethal mutations are mutations that lead to the death of the individual. Death does not have to occur immediately, it may take several months or even years. But if the expected longevity of an individual is significantly reduced, the mutation is considered a lethal mutation.

Wild type alleles typically encode a product necessary for a specific biological function. If a mutation occurs in that allele, the function for which it encodes is also lost. The general term for these mutations is loss-of-function mutations. The degree to which the function is lost can vary. If the function is entirely lost, the mutation is called a null mutation. If is also possible that some function may remain, but not at the level of the wild type allele. These are called leaky mutations.

Loss-of-function

Loss-of-function mutations are typically recessive. When a heterozygote consists of the wild-type allele and the loss-of-function allele, the level of expression of the wild type allele is often sufficient to produce the wild type phenotype. Genetically this would define the loss-of-function mutation as recessive. Alternatively, the wild type allele may not compensate for the loss-of-function allele, and the gene is called haploinsufficient. In those cases, the phenotype of the heterozygote may be equal to that of the loss-of-function mutant, and the mutant allele will act as a dominant.

Gain-of-function

Gain-of-function mutations create a new allele that is associated with a new function. Any heterozygote containing the new allele along with the original wild type allele will express the new allele. Genetically this will define the mutation as a dominant.

Sickle hemoglobin, where the function of the hemoglobin has changed in a way to be not conducive to malariaparasites, is often cited as an example of a gain-of-function mutation, but it is actually a loss-of-function mutation that conveys a survival advantage in some circumstances. A proper example is the mutations that occur in the immune system in order to make and improve antibodies against invading bacteria and viruses.

This is good evidence that natural selection plays a part in maintaining a higher frequency of this carrier state. If you are resistant to malaria, you are more likely to survive to pass on your genes. Nevertheless, it is a defect, not an increase in complexity or an improvement in function which is being selected for, and having more carriers in the population means that there will be more people suffering from this terrible disease.[1]

HIV-1 M subtype D's Na+ viroporin, is known as an example of a Gain-of-Function mutation due to the viroporin being gated and specific to Na+ cations. A viroporin is an ion channel that allows for the movement of ions from one side of a membrane to another. A gated channel has an additional feature which closes the channel to prevent "leaking" of ions across the membrane. In this example the HIV types before HIV-1 M did not have this viroporin. To go from an ordinary viroporin's original form to the multisubunit structure with a new function required the development of a new binding site, which involves more than a single amino acid substitution.[2] Not just any binding site will do, for a mass of agglomerated protein would occur, not an ion channel with ion selectivity. As such, HIV-1 M's viroporin is a gated ion channel, not just a hole punched in the membrane, with a specific amino acid responsible for the gating.[3] What is important is that this mutation is beneficial to the virus; it increases viral particle release, spreading HIV more efficiently.[2]

Neutral

Neutral mutations cause neither a gain or a loss of function. For example, both AAA and AAG code for the amino acid lysine, so a mutation (a single-letter substitution) of one to the other would be predicted to have no effect. Gene duplications can also be initially neutral, and then later turn out to protect the organism if one of the genes (which has a redundant function after the duplication) is mutated later on.

Nonsense

Nonsense mutations cause introduction of a stop codon into a gene, which will then be produced only in a truncated form. Nonsense mutations are almost always loss-of-function mutations as well.

Dynamic

Dynamic mutations are heritable mutations where the probability of the mutation is a function of the number of copies of the mutation, causing the chance of inheriting the mutation to be different than organism’s predecessor. These mutations are known to cause several genetic syndromes such as Fragile X syndrome, Huntington’s Chorea, Myotonic Dystrophy and Creutzfeldt-Jakob Disease to name a few.

Frame shift

Frame shift mutations are mutations where the reading frame is moved to cause a different translation of the DNA. This is due to the fact that codons that encode the genetic sequence are read in threes. Frame shift mutations are known to cause hypercholesterolemia as well as disabling several chemokine receptors.

Reversions

Reversion mutations are those which "undo" a previous mutation by chance (for example, a mutation of ATG to CTG in the start codon of a gene will prevent it from being transcribed, but a mutation at the same location might undo this back to ATG). A mutation at another location might also revert the phenotype (for example, if another gene which compensates for the lost function of the first is upregulated), although the genetic code is still different from before the two mutations had occurred.

Mutations that allegedly create new genetic information have been described. Mutations are claimed to have led to the evolution of new genes,[6] to the novel use of existing genetic information,[7] and to the construction of new genes by shuffling and recombining of parts of existing genes,[8] although the claims are disputed[9] or are based on speculation rather than observation of the mutations actually occurring. But these examples don't challenge creation at all, since the information already existed in the past. Mutations that have created new genetic information (different from genetic material) have never been observed.

Some contemporary biologists, as soon as they observe a mutation, talk about evolution. They are implicitly supporting the following syllogism: mutations are the only evolutionary variations, all living beings undergo mutations, therefore all living beings evolve....No matter how numerous they may be, mutations do not produce any kind of evolution.[10]

Grasse went on to point out that bacteria, much studied by geneticists and molecular biologists, produce the most mutants,[11] yet bacteria are considered to have "stabilized a billion years ago!".[10]
Grasse regards the "unceasing mutations" to be "merely hereditary fluctuations around a median position; a swing to the right, a swing to the left, but no final evolutionary effect."[10]

Although he believed that random mutations produced new features, Harvard biologist Ernst Mayr admitted the difficulty with the idea: "It must be admitted, however, that it is a considerable strain on one’s credulity to assume that finely balanced systems such as certain sense organs (the eye of vertebrates, or the bird’s feather) could be improved by random mutations."[12]